rs2419244

Positions:

• chr19-13311910-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127222.2(CACNA1A):​c.1668+759T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 152,102 control chromosomes in the GnomAD database, including 7,170 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7170 hom., cov: 32)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.366

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1668+759T>C		intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1668+759T>C		intron_variant		1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44659 AN: 151984 Hom.: 7151 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.290

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.294 AC: 44720 AN: 152102 Hom.: 7170 Cov.: 32 AF XY: 0.293 AC XY: 21773 AN XY: 74390

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.292

Alfa AF: 0.260 Hom.: 949

Bravo AF: 0.306

Asia WGS AF: 0.428 AC: 1490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.6
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2419244; hg19: chr19-13422724;